Sino-atrial node modulating pyrrolopyrimidines

Abstract

This invention concerns novel heterocyclic compounds of formula I (and pharmaceutically-acceptable salts thereof); <IMAGE> I wherein: R1 is hydrogen, (1-8C)alkyl or phenyl(1-4C)alkyl; R2 is (1-6)alkyl, phenyl(1-4C) alkyl, (3-6C)cycloalkyl, (3-6C) cycloalkyl(1-4C)alkyl, (3-6C)cycloalkyl, phenyl(1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl or (3-6C)alkenyl; R4 and R5 are independently selected from hydrogen and (1-6C)alkyl; and wherein the phenyl ring and/or one or more of said phenyl or benzene moieties may optionally be unsubstituted or substituted by one or more substituents independently selected from halogeno, (1-4C)alkyl, (3-6C)alkenyl, (1-4C)alkoxy, cyano, trifluoromethyl, nitro, carboxy, (1-4C)alkylamino, dialkylamino of up to six carbon atoms, (1-4C)alkylthion, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (1-4C)alkylsulphonyl and (1-4C)alkylenedioxy; but excluding the compound in which R1, R3, R4 and R5 are each methyl, the phenyl ring is unsubstituted and R2 is ethyl, and its pharmaceutically-acceptable salt. The compound of formula I (and pharmaceutically-acceptable salts thereof) possess beneficial effects on the cardiovascular system, and in particular beneficial effects modulated via the sino-atrial node. Also included are processes for the manufacture of compounds of the formula I (or a pharmaceutically-acceptable salt), and pharmaceutical compositions.

I claim: 
     
       1. A compound of formula I or a pharmaceutically-acceptable salt thereof, wherein:   R 1  is hydrogen, (1-8C)alkyl or phenyl(1-4C)alkyl;   R 2  is (1-6C)alkyl, (3-6C)cycloalkyl or   (3-6C)cycloalkyl(1-4C)alkyl;   R 3  is hydrogen, (1-6C)alkyl, phenyl (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl or (3-6C)alkenyl;   R 4  and R 5  are independently selected from hydrogen and (1-6C)alkyl; and wherein the phenyl ring shown in formula I and/or one or more of said phenyl moieties recited as R 1  or R 3  [or benzene moieties] may optionally be unsubstituted or substituted by one or more substituts independently selected from halogeno, (1-4C)alkyl, (3-6C)alkenyl, (1-4C)alkoxy, cyano, trifluoromethyl, mitro, carboxy, (1-4C)alkylamino, dialkylamino of up to six carbon atoms, (1-4C)alkythion, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (1-4C)alkylenedioxy; but excluding the compound in which R 1 , R 3 , R 4  and R 5  are each methyl, the phenyl ring is unsubstituted and R 2  is ethyl, and its pharmaceutically-acceptable salts.     
     
     
       2. A compound as claimed in claim 1 wherein: R 1  is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, bensyl, 1-phenylethyl or 2-phenylethyl;   R 2  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,;   R 3  is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, benzyl, 1-phenylethyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, allyl, but-2-enyl, but-3-enyl, 2-methyl-2-propenyl, pentenyl or phenyl; R 4  and R 5  are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl; and wherein the phenyl ring shown in formula I and/or one or more of said phenyl moieties recited as R 1  or R 3  may optionally be unsubstituted or substituted by one or more substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, allyl, 2-methyl-2-propenyl, methoxy, ethoxy, propoxy, cyano, trifluoromethyl, nitro, carboxy, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethlsulphonyl, methylenedioxy, isopropylidenedioxy.   
     
     
       3. A compound as claimed in claim 1 wherein: R 1  is (1-6C)alkyl or benzyl; R 2  is (1-6C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl, or benzyl; R 3  is (1-6C)alkyl; and wherein the phenyl ring and/or the phenyl moiety of the benzyl group is unsubstituted or is substituted by one or more substituents independently selected from halogeno, (1-4C)alkyl, (3-6C)alkenyl, (1-4C)alkoxy, cyano, trifluoromethyl, nitro, carboxy, (1-4C)alkylamino, dialkylamino of up to six carbon atoms, (1-4C)alkylthion, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (1-4C)alkylenedioxy. 
     
     
       4. A compound as claimed in claim 1 or 2 wherein: R 1  is hydrogen or (1-6C)alkyl; R 2  is (1-4C)alkyl; R 3  is hydrogen or (1-4C)alkyl; R 4  and R 5  are independentendly selected from hydrogen and (1-4C)alkyl; and wherein the phenyl ring may optionally be unsubstituted or substituted by one or two substituents independently selected from halogeno, (1-4C)alkyl, and (1-4C)alkoxy. 
     
     
       5. A compound of formula I or a pharmaceutically-acceptable salt thereof, ##STR3## wherein: R 1  is hydrogen, (1-8C)alkyl or phenyl(1-4C)alkyl; R 2  is methyl;   R 3  is hydrogen, (1-6C)alkyl, phenyl(1-4C), (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl or (3-6C)alkenyl; R 4  and R 5  are independently selected from hydrogen and (1-6C)alkyl; and wherein the phenyl ring shown in formula I and/or one or more of said phenyl moieties recited as R 1  or R 3  may optionally be unsubstituted or substituted by one or more substituents independently selected from halogen, (1-4C)alkyl, (3-6C)alkenyl, (1-4)alkoxy, cyano, trifluoromethyl, nitro, carboxy, (1-4C)alkylamino, dialkylamino of up to six carbon atoms, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (1-4C)alkylenedioxy.   
     
     
       6. A compound as claimed in claim 5 wherein: R 1  is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; R 2  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl;   R 3  is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl; R 4  and R 5  are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl; and wherein the phenyl ring shown in formula I may optionally be unsubstituted or substituted by one or more substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, methoxy, ethoxy or propoxy.   
     
     
       7. A compound as claimed in claim 1 which is selected from: 2,3-dimethyl-4-methylimino-7-phenyl-3H,7H-pyrrolo [2,3-d]pyrimidine;   2,3,5,6-tetramethyl-4-methylimino-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidine;   2,3,5,6-tetramethyl-4-imino-7-phenyl-3H, 7H-pyrrolo-[2,3-d]pyrimidine;   2,3,5,6-tetramethyl-4-n-propylimino-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidine;   2,3,5,6-tetramethyl-4-ethylimino-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidine;   2,3,5,6-tetramethyl-4-n-hexylimino-7-phenyl-3H,7H-pyrrolo-[2,3d]pyrimidine;   3,5,6-trimethyl-4-imino-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidine;   
     
     
       8. A compound as claimed in claim 1 which is in the form of a salt selected from chloride, bromide, iodide, sulphate, nitrate and trifluoracetate. 
     
     
       9. A pharmaceutical composition comprising a compound as claimed in claim 1 or claim 5, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
       10. A method of modulating the action of the sino-atrial node in a warm-blooded animal requiring such treatment which comprises administering to said animal an effective amount of a pharmacologically active agent comprising a compound of the formula I or a pharmaceutically-acceptable salt thereof, ##STR4## wherein: R 1  is hydrogen, (1-8C)alkyl or phenyl(1-4C)alkyl; R 2  is (1-6C)alkyl, phenyl, phenyl(1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-4C)alkyl;   R 3  is hydrogen, (1-6C)alkyl, phenyl(1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, phenyl or (3-6C)alkenyl;   R 4  and R 5  are independently selected from hydrogen and (1-6C)alkyl; and wherein the phenyl ring shown in formula I and/or one or more of said phenyl moieties recited as R 1  or R 3  may optionally be unsubstituted or substituted by one or more substituents independently selected from halogeno, (1-4C)alkyl, (3-6C)alkenyl, (1-4C)alkoxy, cyano, trifluoromethyl, nitro, carboxy, (1-4C)alkylamino, dialkylamino of up to six carbon atoms, (1-4C)alkythio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (1-4C)alkylenedioxy; but excluding the compound in which R 1 , R 3 , R 4  and R 5  are each methyl, the phenyl ring is unsubstituted and R 2  is ethyl, and its pharmaceutically-acceptable salts.